Year: 2024
Type: article
Abstract: BACKGROUND: Mas-related G protein-coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. OBJECTIVE: We sought to identify and characterize novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. METHODS: transgenic human MRGPRX2 knock-in mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. RESULTS: MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 knock-in mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. CONCLUSIONS: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.
Authors: Joshua Wollam, Michelle Solomon, Christiane Villescaz, Marion Lanier, Samantha Evans, Corinne Bacon, David Freeman, Alexis Vasquez, Alan Vest, Jim Napora, Brittney Charlot, Christine Cavarlez, Andrew Kim, Lisa Dvorak, Brandon Selfridge, Liming Huang, Andres Nevarez, Harry Dedman, Jennifer Brooks, Stefan Frischbutter, Martin Metz, Nadine Serhan, Nicolas Gaudenzio, Gregg Timony, Esther Martinborough, Marcus F. Boehm, Veena Viswanath
Language: English
Topic: Mast cells and histamine
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
Funder: National Institutes of Health
OpenAlex ID: W4400370518